Yin Hubin, Yang Xiaoyu, Gu Wen, Liu Yan, Li Xinyuan, Huang Xiaolong, Zhu Xin, Tao Yong, Gou Xin, He Weiyang
Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Oncotarget. 2017 May 11;8(42):71642-71656. doi: 10.18632/oncotarget.17796. eCollection 2017 Sep 22.
High-mobility group box 1 (HMGB1) has been found to mediate autophagy during chemotherapy in several cancers. However, whether HMGB1plays a role in autophagy and chemoresistance in bladder cancer is elusive. In this report, HMGB1 expression was found to be increased in 30 primary bladder cancer tissue specimens compared to their matched adjacent non-tumor tissues. While gemcitabine induced apoptotic cell death, it also induced HMGB1 expression and autophagy in bladder cancer T24 and BIU-87 cells. Suppressing HMGB1 expression with siRNA strongly potentiated gemcitabine-induced apoptosis. HMGB1 siRNA or autophagy inhibitors suppressed gemcitabine-induced autophagy. Further, gemcitabine activated c-Jun N-terminal kinase (JNK) and extracellular regulated protein kinase (ERK) and Bcl-2 phosphorylation, and blocking ERK and JNK inhibited autophagy and increased apoptosis in gemcitabine-treated cells. Interestingly, suppressing HMGB1 expression attenuated gemcitabine-induced ERK and JNK activation and Bcl-2 phosphorylation. Thus, our results suggest that while gemcitabine kills bladder cancer cells through apoptosis, a cytoprotective autophagy is also induced involving HMGB1-mediated JNK and ERK to counteract the cytotoxicity of gemcitabine, and intervention targeting this pathway may improve the anticancer efficacy of gemcitabine against bladder cancer.
高迁移率族蛋白B1（HMGB1）已被发现在多种癌症的化疗过程中介导自噬。然而，HMGB1在膀胱癌的自噬和化疗耐药中是否发挥作用仍不清楚。在本报告中，与配对的相邻非肿瘤组织相比，在30例原发性膀胱癌组织标本中发现HMGB1表达增加。吉西他滨诱导凋亡性细胞死亡的同时，也诱导膀胱癌T24和BIU - 87细胞中HMGB1表达和自噬。用小干扰RNA（siRNA）抑制HMGB1表达可强烈增强吉西他滨诱导的凋亡。HMGB1 siRNA或自噬抑制剂可抑制吉西他滨诱导的自噬。此外，吉西他滨激活c - Jun氨基末端激酶（JNK）和细胞外调节蛋白激酶（ERK）以及Bcl - 2磷酸化，阻断ERK和JNK可抑制吉西他滨处理细胞中的自噬并增加凋亡。有趣的是，抑制HMGB1表达可减弱吉西他滨诱导的ERK和JNK激活以及Bcl - 2磷酸化。因此，我们的结果表明，虽然吉西他滨通过凋亡杀死膀胱癌细胞，但也诱导了一种细胞保护性自噬，涉及HMGB1介导的JNK和ERK以抵消吉西他滨的细胞毒性，针对该途径的干预可能会提高吉西他滨对膀胱癌的抗癌疗效。
